The Effect of Anti-coagulation Dosage on the Outcome of Hospitalized COVID-19 Patients in Ethiopia

A Multi-Center Retrospective Cohort Study

Abel Girma Tessema; Zekarias Masresha Mengiste; Tsegaye Gebreyes Hundie; Hailemichael Getachew Yosef; Dawit Kebede Huluka; Abebaw Bekele Seyoum; Hannibal Kassahun Abate; Rawleigh Craig Howe

Disclosures

BMC Pulm Med. 2023;23(85)

Methods

Study Design and Setting

A health facility based retrospective multi-center cohort study comparing clinical outcomes in patients who received prophylactic anticoagulation and therapeutic anticoagulation was conducted by reviewing patients' charts in the three largest COVID-19 treatment facilities in Addis Ababa, Ethiopia. The facilities included Eka-Kotebe General Hospital (EKGH), Millennium COVID-19 Care Center (MCCC) and Bulbula COVID-19 Field Hospital under St. Peter's Specialized Hospital (BFH). The data were obtained from the medical records of patients admitted at the study sites from April 15^th 2020 to January 15^th 2022.

Sampling Procedure and Eligibility Criteria

A study conducted in an Ethiopian hospital with a setting similar to ours reported a mortality rate of 28.6% among hospitalized COVID-19 patient.^[22] Assuming a mortality rate of 25–30%, equal numbers of patients given therapeutic and prophylactic anticoagulation, a power of 0.8, and a 10–15% difference between the groups, we calculated a required sample size of 234–252 patients per group. Based on the total case load since the onset of COVID on each study site, a 2:2:1 proportion (EKGH: MCCC: BFH) was used to determine the sample size at each respective study site. In selection of the study patients, a simple random sampling technique was applied using the HMIS (Health Management Information System) at each study site as a sampling frame.

In all included patients, COVID-19 was confirmed by a positive polymerase chain reaction (PCR) test. In addition, all included patients were above 18 years of age by the time they were admitted to the hospital. On the day of hospital admission, all patients received either therapeutic or prophylactic dose pharmacological thromboprophylaxis, and the same regimen was followed for at least 7 days. The anticoagulation medications used were mainly unfractionated heparin (UFH) and the low molecular weight heparin (LMWH), enoxaparin. Other anticoagulants used were rivaroxaban and warfarin. The decision to put patients on which anticoagulant regimen was primarily based on local hospital guidelines and judgement of attending physicians, which varied frequently throughout the course of the period. We excluded patients who had any contraindication for anticoagulation, patients who were receiving anticoagulation therapy prior to the diagnosis of COVID-19 for other medical indication, patients who were diagnosed with thrombosis during or prior to hospitalization, or patients who did not have complete medical charts, including documented history, physical examination, investigation and management recorded throughout their hospital stay.

Data Collection and Quality Assurance

The data were collected using a pre-tested data collection tool guided by the reports of the ACTION randomized trial.^[6] The tool was modified and commented by experienced pulmonologist and internal medicine specialists to ensure convenience in the setting. A pilot study was conducted on 25 patients from May 01, 2022—May 31, 2022, and modified appropriately including removal of unnecessary variables. The final data collection tool had four parts. The first part included demographics (age, gender, occupation) and hospital number. In the second part, patients' baseline and admission characteristics were recorded, including variables such as vaccination status, presence of chronic co-morbid conditions (hypertension, diabetes, ischemic heart disease, heart failure, stroke, asthma, chronic kidney disease, chronic liver disease, HIV/AIDS, malignancies, and smoking), risk factors for thrombosis (based on the Well's score), patients' symptoms, physical findings, investigation results and management initiated at admission. In the third part, any significant changes that occurred during patients' hospital stay including development of new symptoms, new physical findings, pertinent investigation findings, new diagnoses, new treatment initiated were recorded. In the final part, outcome of the patients and patients' status on the day of the outcome were recorded. All-cause in-hospital mortality was the primary outcome variable, and length of hospital stay and thrombotic events were secondary outcome variables. As a safety outcome, we included bleeding complications.

In Ethiopia, different types of COVID-19 vaccines with differing schedules were administered, including Pfizer/BioNTech, AstraZeneca (Oxford), Janssen (Johnson & Johnson), and the Sinopharm vaccine. Although vaccination status was recorded upon admission and most patients specified the number of doses they took, they were mostly unaware of the specific vaccine type they received, making it challenging to determine the complete vaccination status of our study subjects. Hence, we resorted to categorizing patients as those who took at least one dose of vaccine and those who didn't receive any.

Eight experienced and trained data collectors (all general practitioners working as clinicians in the study sites) collected the data from April 2022—July 2022. We utilized REDCap software for on-site electronic data collection, cleaning and management of the collected database. The data collectors were trained about the entire process of data collection including quality control measures such as: completeness, correctness, consistency, and synchronizing and archiving data with REDCap. Regular supervision and follow-up were made by the principal investigator throughout the data collection period. Completeness, correctness and consistency of the reviewed data were checked on a daily basis by supervisors. The overall activities and entire process of data collection were led by the principal investigator. The data collection process followed the standard national infection prevention and control protocol for COVID-19.

Operational Definitions

The definition and classification of COVID-19 was primarily based on the third edition of the national comprehensive COVID-19 clinical management handbook for Ethiopia with some modifications.^[13]

Confirmed COVID-19 case: A person with a laboratory confirmation of COVID-19 infection using a real-time polymerase chain reaction test (RT PCR test), irrespective of clinical signs and symptoms.

Severe COVID 19 illness: Confirmed COVID-19 patients receiving oxygen supplementation with either nasal cannula or simple face-mask but not requiring face-mask with reservoir.

Critical COVID 19 illness: Confirmed COVID-19 patients requiring oxygen supplementation with reservoir face-mask or mechanical ventilation or patients with respiratory failure, septic shock, and/or multiple organ dysfunctions (MOD) or failure (MOF) and needing invasive or special management.

Thrombotic complications (events): include the development of either arterial (acute myocardial infarction, acute limb ischemia, mesenteric ischemia, cerebral infarction, aortic thrombosis) or venous (pulmonary thromboembolism, deep vein thrombosis) thrombotic disorder.^[6] Unless otherwise specified, thrombotic events refer to patients where the diagnosis of thrombosis was supported by definitive investigation modalities (i.e., definitive thrombosis).

Clinically diagnosed thrombosis: diagnosis of thrombotic complication evidenced by patient's clinical presentation but not necessarily confirmed by definitive investigation modality.

Definitively diagnosed thrombosis: diagnosis of thrombotic complication confirmed by definitive investigation modality.

Prophylactic anticoagulation dosage: include either of the following anticoagulation regimens:

For patients with body mass index (BMI) < 40 kg/m2 → LMWH: (Enoxaparin 40 mg SC daily) or UFH 5000 IU SC (subcutaneously) TID (three times a day) or UFH 7500 IU SC BID (twice a day),
For patients with BMI > 40 kg/m2 → Enoxaparin 40 mg SC BID,
For patients with BMI ≥ 50 kg/m2 → Enoxaparin 60 mg SC BID and.
For patients with creatinine clearance < 30 mL/min → Enoxaparin 30 mg SC daily.

Therapeutic anticoagulation dosage: include either of the following anticoagulation regimens:

Enoxaparin 1 mg/kg SC BID (60 mg SC BID) for 45 days or UFH 5000 IU IV/SC bolus and then 17,500 IU SC BID until patient discharge with subsequent prescribed shift to oral anticoagulants, rivaroxaban 15 mg PO BID for 21 days, then 20 mg PO daily, or warfarin (three days overlap) dose adjusted to INR 2–3 for a total of 42 days.

Major or minor clinically significant bleeding.^[23]

(Adopted from International Society on Thrombosis and Hemostasis (ISTH) Definition).

Include one of the following: Fatal bleeding and/or Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome or Bleeding causing a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or red cells.

Statistical Analysis

All statistical analyses were performed using IBM Statistical Package for Social Sciences (SPSS) version 26 (IBM Corporation, Armonk, NY, USA). Continuous variables were analyzed using Mann Whitney U test and findings were reported as medians and interquartile ranges (IQR). Categorical variables were compared using Chi square for variables with high expected values and Fisher's exact test for those with low expected values. Our primary outcome variable was all-cause in-hospital mortality. We used multivariable binary regression model to calculate the adjusted odds ratio. Additionally, a Cox proportional hazard model was used to see the effect of how different covariates impacted the time to death. Findings were reported as adjusted hazard ratio (AHR) with 95% confidence interval (CI). A Cox regression survival plot was also done stratified by COVID-19 severity at admission. Again, we used the Cox proportional hazard model to compare length of hospital stay, censoring patients who were transferred to another health facility and those who died in hospital. A p-value of less than 0.05 was considered statistically significant and all values were reported with a 95% CI.

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Table 1. Demography, baseline characteristics and clinical variables of hospitalized COVID-19 patients in Ethiopia
		Prophylactic anticoagulation (n = 237)	Therapeutic anticoagulation (n = 235)	p-value
Hospital	Eka-Kotebe General Hospital	83 (35.0%)	91 (38.7%)	0.648
	Millennium COVID-19 Care Center	99 (41.8%)	96 (40.9%)
	COVID-19 St. Peter's Field Hospital	55 (23.2%)	48 (20.4%)
Age in years, median (IQR)		59.00 (45.5 – 67.0)	60.00 (48.0 – 67.0)	0.711
Gender	Male, n (%)	154 (65.0%)	135 (57.4%)	0.108
Gender	Female, n (%)	83 (35.0%)	100 (42.6%)	0.108
Comorbidity, n (%)
Hypertension		85 (35.9%)	83 (35.3%)	0.924
Diabetes Mellitus		76 (32.1%)	74 (31.5%)	0.921
HIV/AIDS		11 (4.6%)	12 (5.1%)	0.834
Asthma		10 (4.2%)	13 (5.5%)	0.508
Stroke		7 (3.0%)	5 (2.1%)	0.772
Malignancy		2 (0.84%)	5 (2.1%)	0.284
Ischemic Heart Disease		3 (1.3%)	4 (1.7%)	0.724
Prior history of Tuberculosis		2 (0.8%)	5 (2.1%)	0.284
Chronic Kidney Disease		4 (1.69%)	1 (0.43%)	0.372
Chronic Liver Disease		2 (0.8%)	1 (0.43%)	1.000
Schizophrenia		0 (0.0%)	3 (1.3%)	0.123
Smoking, n (%)		3 (1.3%)	6 (2.6%)	0.337
COVID-19 Severity at admission, n (%)
Severe		147 (62.0%)	133 (56.6%)	0.261
Critical		90 (38.0%)	102 (43.4%)	0.261
Type of Oxygen therapy used at admission, n (%)				0.021
Nasal cannula		107 (45.1%)	80 (34.0%)
Simple Face mask		40 (16.9%)	53 (22.6%)
Face mask with reservoir		28 (11.8%)	41 (17.4%)
Non-invasive ventilation		53 (22.4%)	44 (18.7%)
Invasive ventilation		9 (3.8%)	17 (7.2%)
Vital Sign, median (IQR)
Heart rate, bpm		94.00 (86.0 – 106.0)	94.00 (83.0 – 105.0)	0.221
Respiratory rate, rate/min		28.00 (24.0 – 32.0)	31.00 (26.0 – 36.0)	< 0.001
Diastolic blood pressure, mm Hg		75.00 (67.0 – 83.5)	72.00 (65.0 – 80.0)	0.095
Systolic blood pressure, mm Hg		126.00 (111.5 – 145.0)	129.00 (112.0 – 142.0)	0.958
Laboratory values, median (IQR)
Hemoglobin, g/dL		14.10 (13.0 – 15.5)	14.05 (13.0 – 15.3)	0881
Hematocrit, %		41.60 (38.4 – 45.2)	42.00 (38.5 – 45.0)	0.553
Total WBC count, × 10 ³/mL		9.60 (6.4 – 11.9)	8.94 (6.4 – 13.1)	0.831
Neutrophil, %		87.50 (81.0 – 92.0)	89.85 (81.5 – 92.4)	0.144
Lymphocyte, %		6.35 (3.7 – 10.4)	6.30 (3.9 – 10.6)	0.745
Platelet count, 10 ⁹/L		244.50 (175.8 – 315.0)	234.00 (167.5 – 310.8)	0.622
Alanine aminotransferase, U/L		40.60 (25.6 – 65.1)	31.95 (22.8 – 62.5)	0.479
Aspartate aminotransferase, U/L		40.95 (29.1 – 62.2)	38.00 (27.1 – 60.1)	0.887
Creatinine, mg/dL		0.72 (0.62 – 0.90)	0.80 (0.60 – 1.0)	0.112
Urea, mg/dL		32.50 (21.3 – 46.5)	24.30 (16.1 – 37.1)	0.001
Sodium, mmol/L		138.00 (134.0 – 140.0)	137.00 (133.0 – 140.0)	0.456
Potassium, mmol/L		4.26 (3.90 – 4.70)	4.10 (3.70 – 4.60)	0.055

Table 2. Binary logistic regression analysis with odds ratio for in-hospital mortality
		Inpatient mortality, n (%)	Total	Crude OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value
Age	< 60 yrs	66 (24.1%)	274
Age	> 60 yrs	88 (44.4%)	198	2.52 (1.70–3.74)	< 0.001	2.74 (1.60–4.69)	< 0.001
Vaccine status	Not received	149 (33.7%)	442
Vaccine status	Received at least 1 dose	5 (16.7%)	30	0.39 (0.15–1.05)	0.062	0.23 (0.07–0.84)	0.025
Hypertension	No	89 (27.4%)	304
Hypertension	Yes	65 (38.0%)	168	1.52 (1.03–2.27)	0.037	1.52 (0.87–2.65)	0.139
History of Stroke	No	148 (32.2%)	460
History of Stroke	Yes	6 (50.0%)	12	2.11 (0.67–6.65)	0.203	2.44 (0.47–12.52)	0.286
Malignancy	No	148 (31.8%)	465
Malignancy	Yes	6 (85.7%)	7	12.85 (1.53–107.71)	0.019	19.70 (1.52–255.44)	0.023
COVID-19 Severity	Severe	25 (8.9%)	280
COVID-19 Severity	Critical	129 (67.2%)	192	20.56 (12.55–34.76)	< 0.001	23.37 (13.45–40.62)	< 0.001
Anticoagulation dosage	Prophylactic	66 (27.8%)	237
Anticoagulation dosage	Therapeutic	88 (37.4%)	235	1.55 (1.05–2.29)	0.027	1.70 (1.02–2.84)	0.042

Table 3. Cox proportional hazard model for in-hospital mortality
	Crude HR (95% CI)^a	p-value	Adjusted HR (95% CI)^a	>p-value
Age^b	1.03 (1.02—1.04)	< 0.001	1.03 (1.02—1.04)	< 0.001
Vaccination Status	0.52 (0.21—1.26)	0.145	0.43 (0.17—1.06)	0.067
Hypertension	1.48 (1.07 – 2.04)	0.017	1.25 (0.90—1.75)	0.188
COVID-19 Severity	6.63 (4.31 – 10.10)	< 0.001	9.03 (4.30 – 18.99)	< 0.001
Anticoagulation dosage	1.23 (0.89 – 1.69)	0.215	1.41 (1.01 – 1.96)	0.042

^aHazard ratios of in-hospital mortality before and after adjusting for potential confounders given (only variables with p < 0.25 in univariate analysis are included)
^bAll independent variables are categorical except age which is continuous

Table 4. Cox regression analysis for length of hospital stay
Covariates	Severe		Covariates	Critical
Covariates	Adjusted HR (95% CI)	p-value	Covariates	HR (95% CI)	p-value
Anticoagulation dosage	0.76 (0.59 – 0.98)	0.033	Anticoagulation dosage	0.61 (0.36 – 1.04)	0.069
Age	0.99 (0.98 – 1.00)	0.047
Gender (male sex)	1.21 (0.93 – 1.58)	0.151
Stroke	0.32 (0.12 – 0.88)	0.027

Left: subgroup analysis for severe patients, Right: subgroup analysis for critical patients. (Variables with p < 0.25 in univariate analysis are included)